There is a fundamental knowledge gap in understanding how dermal papilla cells (DPCs) instruct the heterogeneous follicular stem cells (SCs) to react in a synchronized manner for a healthy hair growth. The hair follicle is a self-renewing mini-organ supported by the proliferation and differentiation of follicular SCs of different lineages, including epithelial stem cells (EpSCs) and melanocyte stem cells (MSCs). Continued existence of this gap limits our ability to design the effective strategies for the treatment of hair growth disorder, and for the regeneration of hair follicles in cases of congenita hair loss or skin wounds. The long-term goal of my research is to discover the molecular pathways in DPCs that could be manipulated for hair regeneration and pigmentation. The overall objective in this application is to characterize the Wnt/-catenin signaling loop by which DPCs interact with and guide follicular SCs and their progeny to promote hair growth. Wnt/-catenin signaling activity is indispensable for the coordinated activation of EpSCs and MSCs at anagen onset. Wnt proteins can also prolong the ability of isolated DPCs to induce hair. However the origin and nature of the endogenous Wnt signals to initiate these activities remain unidentified. Our central hypothesis is that specific Wnt proteins are first generated in DPCs at anagen onset as an autocrine signal, and subsequently function in a reciprocal signaling loop to orchestrate the activation of follicular SCs to rebuild pigmented hair. The rationale is that the successful completion of the proposed research will provide detailed characterization of the nature of Wnt proteins from DPCs and the mechanism by which the Wnt/-catenin signaling in DPCs guide follicular SCs and their progeny through the normal cyclic growth of hair follicles. This hypothesis will be tested by pursuing three specific aims: 1) identify the DPC populations that respond to Wnt/-catenin signals during the postnatal hair cycle; 2) determine whether Wnt proteins from DPCs are required to activate Wnt/-catenin signaling in the postnatal hair cycle and to induce and sustain hair growth and pigmentation; and 3) determine whether the activation of Wnt/-catenin signaling in DPCs is sufficient to regulate the initiation and maintenance of postnatal hair growth and pigmentation. Our proposed research is innovative because we are the first to engineer an in vivo mouse model system to probe the nature of Wnt proteins from DPCs and their role as an activating signal to prime DPCs for hair induction and activate follicular EpSCs and MSCs in a synchronized manner. The contribution from this proposed research is significant because it will deepen our understanding of the role of DPCs as a signaling center in the regulation of pigmented hair growth and may ultimately permit the development of novel strategies for regenerating hair follicles in cases of severe skin wounds and for the treatment of hair growth disorders. Ultimately, the knowledge obtained from our research will also contribute to a broader and deeper understanding of stem cell biology and tissue engineering. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because understanding of the molecular mechanisms that regulate stem cell activities in hair follicle holds the key to develop the effective strategies for the treatment of hair growth disorders and the regeneration of hair follicles for transplanted skin. Thus, the proposed research is relevant to th part of NIH's mission that pertains to developing fundamental knowledge that will aid in the design of innovative approaches for promotion of healthy hair growth.